This invention relates to the recovery of CCI-779 from mother liquors.
CCI-779 (rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid) is an ester of rapamycin, which has demonstrated significant inhibitory effects on tumor growth in both in vitro and in vivo models. CCI-779 binds to and forms a complex with the cytoplasmic protein FKBP, which inhibits an enzyme, mTOR (mammalian target of rapamycin, also known as FKBP12-rapamycin associated protein [FRAP]). Inhibition of mTOR's kinase activity inhibits a variety of signal transduction pathways, including cytokine-stimulated cell proliferation, translation of mRNAs for several key proteins that regulate the G1 phase of the cell cycle, and IL-2-induced transcription, leading to inhibition of progression of the cell cycle from G1 to S. CCI-779 has been demonstrated to be effective in multiple applications, including inhibition of central nervous system cancer, leukemia, breast cancer, prostate cancer, melanoma, gliomas, and glioblastoma.
The preparation and use of hydroxyesters of rapamycin, including CCI-779, is disclosed in U.S. Pat. No. 5,362,718. A regioselective synthesis of CCI-779 is described in U.S. Pat. No. 6,277,983. However, the yield of CCI-779 resulting is only in the range of 70-80%. Still another regioselective synthesis is described in US Patent Publication No. US 2005-0033046 A1. Recrystallization of CCI-779 is necessary in order to obtain crystalline product for use in clinical applications.
What is needed is a process for recovering additional crystalline CCI-779 from the mother liquors obtained as a by-product of CCI-779 crystallization.